This application is to establish a Clinical Center of TrialNet at the Naomi Berrie Diabetes Center at Columbia University. The Naomi Berrie Diabetes Center opened in November 1998 and has participated in the DPT-1 as an affiliate of the University of Miami. The Center provides clinical care for 3000 patients with diabetes and has several active NIH-funded clinical and basic research programs. The Center has access to a diverse population of patients throughout the New York Metropolitan area including minority populations in Washington Heights and Harlem. We are proposing, in collaboration with colleagues at the University of California at San Francisco, a Phase II trial of the anti-CD3 monoclonal antibody (mAb), hOKT3gamma1(Ala-Ala), to test whether this agent will prevent the onset of Type 1 diabetes in high risk individuals. In an ongoing trial of this agent in patients with new onset Type 1 diabetes, we have found that treatment with the drug is safe, and have preliminary evidence that treatment with a 12-day course of mAb can reduce loss of insulin production in the first year of the disease. In the proposed randomized trial, with support from the Autoimmunity Centers of Excellence, we will treat patients with 3 yearly cycles of drug. Based on published data of rates of diabetes in high risk individuals, we anticipate sample sizes (drug and observation) of 32 each and 5 years of follow-up. Studies will be done on samples from patients to determine the effects of the drug treatment in general and specifically on immunologic markers of the disease. These studies will specifically test the hypotheses that the drug 1) Depletes autoreactive T cells, 2) Anergizes and/or changes the phenotype of the autoimmune response, 3) Induces regulatory cells that inhibit progression of disease. These studies will be done in laboratories at Columbia University, Barbara Davis Center, and University of California at San Francisco. The preliminary studies presented establish the ability of The Naomi Berrie Diabetes Center to carry out trials involving patients with Type 1 diabetes. The Center will be able to coordinate with other centers in carrying out future trials of TrialNet.